title: Ureteral selectivity of intravenous β-adrenoceptor agonists in pig model of acute ureteral obstruction: comparison of KUL-7211, a selective β2/β3 agonist, with isoproterenol, terbutaline, and CL-316243.
abstract: OBJECTIVE
  To compare the potency and ureteral selectivity of the selective β(2)/β(3)-adrenoceptor agonist KUL-7211 with those of the nonselective β-adrenoceptor agonist isoproterenol, selective β(2)-adrenoceptor agonist terbutaline, and selective β(3)-adrenoceptor agonist CL-316243, we performed the study using an isolated porcine ureter and a porcine model of acute unilateral ureteral obstruction.
  
  
  METHODS
  The effects of the drugs on the 80-mM KCl-induced contraction of the ureteral segments isolated from male pigs were evaluated using a functional experimental technique. Anesthetized male miniature pigs with complete obstruction of the left lower ureter were used to evaluate the effects of the cumulative intravenous drug administration on the elevated intraureteral pressure and mean blood pressure.
  
  
  RESULTS
  The KCl-induced contractions in the isolated ureter were concentration-dependently attenuated by KUL-7211, isoproterenol, terbutaline, and CL-316243, with a rank order of potency of 6.26, 6.98, 5.41, and 5.41, respectively. In the anesthetized pigs, all 4 drugs reduced the unilateral ureteral obstruction-induced elevated intraureteral pressure in a dose-dependent manner, with KUL-7211 reducing it with a lower hypotensive effect than either isoproterenol or terbutaline. The ureteral selectivity (defined as the ratio of the effective dose to decrease the mean blood pressure by 25% to the effective dose to decrease the intraureteral pressure by 50%) of KUL-7211 (1.5) was significantly greater than that of isoproterenol (0.04) or terbutaline (0.43).
  
  
  CONCLUSIONS
  The present results have demonstrated that in pigs, KUL-7211 is a potent ureteral relaxant with a relatively small hypotensive effect. A selective β(2)/β(3)-adrenoceptor agonist, such as KUL-7211, warrants additional investigation as a potentially useful drug for the promotion of stone passage in patients with urolithiasis.
authors.affiliation: Central Research Laboratory, Kissei Pharmaceutical Company Limited, Azumino-City, Nagano Prefecture, Japan. isao_wanajo@pharm.kissei.co.jp
authors.forename: Isao
authors.initials: I
authors.lastname: Wanajo
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Tomiyama
authors.forename: Yoshinobu
authors.initials: Y
authors.lastname: Yamazaki
authors.forename: Masami
authors.initials: M
authors.lastname: Kojima
mesh_terms: D000085:Acetates / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D000208:Acute Disease; D000318:Adrenergic beta-Agonists / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D000818:Animals; D004149:Dioxoles / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D004195:Disease Models, Animal; D007275:Injections, Intravenous; D007545:Isoproterenol / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D008297:Male; D013552:Swine; D013726:Terbutaline / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D014513:Ureter / Q000378:metabolism*; D014517:Ureteral Obstruction / Q000188:drug therapy*
chemical_list: D000085:Acetates; D000318:Adrenergic beta-Agonists; D004149:Dioxoles; C484908:KUL7211; C076126:disodium (R,R)-5-(2-((2-(3-chlorophenyl)-2-hydroxyethyl)-amino)propyl)-1,3-benzodioxole-2,3-dicarboxylate; D007545:Isoproterenol; D013726:Terbutaline